Due to disease- or age-related circumstances or cosmetic requirements, a large demand has arisen in the field of medicine for filling materials in order to assist skin and muscle properties in an advantageous manner by increasing volume.
2.1 Under-injection of Wrinkles
In order to render possible the advantageous treatment of wrinkles, e.g. wrinkles on the face and hands, it is known to inject filler materials, so-called “fillers”, into the skin. Wrinkles already develop during childhood due to mimicry and at a later age due to physical damage, such as sun, heat, environment and, at an advanced age, due to typical ageing of the skin. In order to fulfil the wish of many patients for a youthful appearance, various methods for treating wrinkles have been established. Firstly chemical denervation e.g. by botulinum toxin A, secondly levelling of the surface and thirdly treatment with “fillers”—in this case the dermis is lined underneath with endogenous or exogenous substances. The present invention describes the novel use of alginates for use as a “filler” substance. A large number of exogenous fillers, which predominantly consist of biological substances, such as collagen or hyaluronic acid, are available in Europe (e.g.: of collagen: Zyderm®, Zyplast®, Atelocollagen®, Resoplast®. Of Hyaluronic acid: Hylaform®, Restylane®, Perlane®, Juvederm®, Rofilan Hylan Gel®, Hyal-System®, Viscontur®). Collagen is a natural protein which keeps human connective tissue elastic. Preparations for under-injection are obtained from human, porcine and bovine collagen. As is known, it is a disadvantage in this context that humans can react allergically to these protein products and allergy tests must therefore necessarily be conducted before use. It is likewise a disadvantage of collagen preparations that collagen can migrate from the injection site into other areas of skin and cause reddening and swelling there (Millikan, 1989, Long term safety and efficacy with Fibrel in the treatment of cutaneous scars, J Dermatol Surg Oncol, 15:837-842).
Hyaluronic acid is a mucopolysaccharide which occurs in almost every part of a living organism, and in particular in the skin. Hyaluronic acid is formed chemically by straight polymer chains having a molecular weight in the range of from several hundred thousand to millions of Daltons, which contain recurring disaccharide units of N-acetylglucosamine and glucuronic acid linked to one another by glycosidic bonds. A large study has shown that the product Restylane®, which is based on hyaluronic acid, gives significantly better results than the collagen preparation Zyderm® (Narins et al., 2003, A randomized, double-blind, multi-center comparison of the efficacy and tolerability of Restylane versus Zyplast for the correction of nasolabial folds. Dermatol. Surg., 29: 588-95). A disadvantage of hyaluronic acid preparations is that for a visible effect the skin must be treated up to three times at short intervals of time. Swellings may occur here, which subside only after 1-2 days.
Complications two to three years post injectionem—at a time at which the materials injected have long been degraded—are known for both hyaluronic acid preparations and of collagenic acid preparations (Hanke et al., 1991, Abscess formation and local necrosis after treatment with Zyderm or Zyplast Collagen Implant. Journal of American Academy of Dermatology, 25 (no. 2, part 1): 319-26; Moscona et al., 1993, An unusual late reaction to Zyderm 1 injections: A challenge for treatment. Plastic and reconstructive surgery, 92: 331-4).
Liquid silicone has likewise be used for a long time for under-injection of wrinkles. Numerous side effects have adversely emerged here, such as e.g. the formation of nodules, periodically recurring cellulitis and the formation of skin ulcers. Treatment with silicone is therefore no longer regarded as advisable (e.g. Edgerton et al., 1976, Indications for and pitfalls of soft tissue augmentation with liquid silicone, Plast. Reconstr. Surg. 58: 157-65).
2.2 Gastro-oesophageal Reflux Disease
Although gastro-oesophageal reflux disease (“GERD”) is a normal physiological phenomenon, it can lead to severe pathophysiological symptoms. Gastro-oesophageal reflux disease describes the reflux of acid, enzymatic liquid from the stomach into the oesophagus. It causes indigestion, belching and vomiting of the gastric acid into the oral cavity or even into the lungs. The consequences of “GERD” are burns in the oesophagus and the formation of ulcers, the normal epithelial tissue being replaced by pathological tissue. In healthy patients, the lower oesophageal sphincter muscle closes after intake of food. In patients suffering from “GERD”, this does not happen, instead the muscle relaxes and the gastric acid can flow into the oesophagus on contraction of the stomach. This is the main cause of “GERD”; other causes are possible.
Statistical data demonstrate that approximately 35% of the American population suffers from indigestion at least once a month, and 5 to 10% of these once a day. Medically confirmed endoscopy studies show that 2% of the American population suffers from “GERD”. The risk of being affected by this increases from the age of 40 (Nebel et al., 1976, Symptomatic gastroesophageal reflux: incidence and precipitating factors, Am. J. Dig. Dis., 21: 953-6). Endoscopically visible reddening are the first indications of “GERD”. An advanced course of the disease can be recognized from destruction of tissue, following by tumorigenesis up to carcinoma (adenocarcinoma of the oesophagus). A diffuse tumorigenesis occurs in 3.5% of patients under the age of 65 and in 20-30% of patients over the age of 65 (Reynolds, 1996, Influence of pathophysiology, severity, and cost on the medical management of gastroesophageal reflux disease. Am J. Health-syst. Pharm 53:5-12).
Attempts to support the sphincter musculature by under-injection of swellable substances, e.g. bovine collagen or Teflon paste, failed because in the course of time the material migrated from the original injection site.
“GERD” is currently in general treated with proton pump inhibitors, with the aid of which the majority of patients can be successfully treated if the dosage is adequate. However, a disadvantage is that because of the high incidence of recurrence after discontinuation of the acid-suppressive therapy, a medicamentous long-term therapy is necessary for a permanent conservative elimination of the symptoms in most patients (Bittinger and Messmann, 2003, Neue endoskopische Therapieverfahren bei gastroösophagealer Refluxkrankheit [New endoscopic therapy methods for gastro-oesophageal reflux disease], Z. Gastroenterol, 41: 921-8). Many patients furthermore are not prepared to take medicaments daily for decades. In addition, there are also the problems of the not inconsiderable cost of such medicamentous long-term therapy.
In addition to open and laparoscopic fundoplication, endoscopic therapy methods have recently been employed, with the aim of addressing the main cause of gastro-oesophageal reflux disease therapeutically, namely the incompetent lower oesophagus sphincter. 3 different basic principles are pursued here, firstly suture techniques (e.g. endoscopic gastroplasty, full wall oplication), secondly radiofrequency application and thirdly injection and implantation methods (e.g. biopolymer injection, implantation therapy). The present invention describes a material for biopolymer injection.
This method is currently carried out with a polymer of ethylene-vinyl alcohol (Enteryx®, Boston Scientific, USA). This is a synthetic polymer which is not biodegradable, is chemically inert, has no antigenic properties and has a permanently spongy-elastic consistency after precipitation in tissue. After dissolving the substance in a solvent (dimethylsulfoxide), it is selectively injected in the liquid state into the oesophagus wall via an endoscopic injection needle under radiological control (support of the musculature, raising of pressure). In the context of a clinical study, it emerged as a disadvantage that in only 60% of the patients more than 50% of the polymer injected was still in situ at the injection site after 6 months, and in some cases even more than 75% of the amount originally injected was no longer detectable (Devière at al., 2002, Endoscopic implantation of a biopolymer in the lower esophageal sphincter for gastro-esophageal reflux: a pilot study. Gastrointes Endsc 2002, 55: 335-41). A migration of the polymers, presumably through the wall into the lumen of the gastrointestinal tract, evidently thus occurs in a considerable proportion of patients in the course of time.
On the basis of the technically comparatively simple method and the results to date, biopolymer therapy seem attractive, although the irreversibility of the method and the migration of the material injected must be regarded critically as disadvantages. The present invention describes a proposed solution to the disadvantages mentioned by the novel use of alginates.
2.3 Urinary Incontinence and Vesico-ureteral Reflux Disease
Urinary incontinence in which an involuntary discharge of urine occurs, can arise as an independent disease or as a concomitant symptom of other diseases. Urinary incontinence, by which over 6 million people are affected in Germany, is often regarded as a taboo subject and is therefore concealed and medical help is scarcely sought. It is therefore difficult to establish precise figures regarding the occurrence of urinary incontinence. Estimates suggest that in Germany about 11% of the over-65s and 30% of the over-80s are affected by urinary incontinence. Among the younger people suffering from incontinence, the proportion of women is predominant. The reason for this is that many women have a weakened musculature of the pelvic floor after pregnancy and childbirth and often too little value is laid on exercising of the pelvic floor after the delivery. At an older age, urinary incontinence often occurs in men as a consequence of benign prostate hyperplasia. In addition to the social pressure of the affliction, patients with urinary incontinence are predisposed towards urinary tract infections, ulcers, rashes and urosepsis. In the USA alone, more than 10 billion US dollars are spent annually on dealing with urinary incontinence.
The causes of urinary incontinence can be diverse, and one cause of this is the muscular weakness of the inner sphincter muscle (m. sphincter urethrae internus) of the bladder musculature. For treatment of urinary incontinence, substances having an anticholinergic action which relax the urinary bladder musculature are extensively administered (e.g. Wein, 1995, Pharmacology of Incontinence, Urol. Clin. North Am., 22: 557-77). The significant side effects of these medicaments are often a disadvantage here.
In addition to medicamentous treatment, surgical methods are employed for therapy of urinary incontinence, e.g. implantation of an artificial sphincter (Lima et al., 1996, Combined use of enterocystoplasty and a new type of artificial sphincter in the treatment of urinary incontinence, J. Urology, 156: 622-4), injection of collagens (Berman et al., 1997, Comparative cost analysis of collagen injection and facia lata sling cystourethropexy for the treatment of type III incontinence in women, J. Urology, 157: 122-4) and polytetrafluoroethylenes (Perez et al., 1996, Submucosal bladder neck injection of bovine dermal collagen for stress urinary incontinence in the pediatric population, Urology, 156: 633-6).
As in the treatment of “GERD”, the use of injectable collagens has the adverse effect that the treatment must often be repeated because of migration of the material (Khullar et al., 1996, GAX Collagen in the treatment of urinary incontinence in elderly women: A two year follow up. British J. Obstetrics & Gynaecology, 104: 96-9) and can lead to the occurrence of allergies (McClelland and Delustro, 1996, Evaluation of antibody class in response to bovine collagen treatments in patients with urinary incontinence, J. Urology, 155: 2068-73).
A cause of vesico-ureteral reflux disease is the reflux of urine through the ureter from the bladder in the direction of the kidney during urination. This disease occurs often in young children. The reflux of urine can permanently damage the kidneys by bacterial contamination, from scarring to loss of one or both kidneys. The way to avoid kidney damage must therefore be to avoid kidney infections. This can be effected on the one hand by long-term prophylactic administration of antibiotics with unforeseeable side effects, or on the other hand by surgical correction of the reflux with all the known risks of a surgical intervention.
Although vesico-ureteral reflux in children subsides again by itself in the course of time, in some cases it leads to serious urinary tract and kidney infections up to renal failure. There is therefore the need for a safe, effective, minimally invasive and long-term method for treatment of this reflux disease. The endoscopic treatment method has various advantages over conventional surgical methods: out-patient treatment, no scarring, low risk of postoperative obstruction and lower costs. Various substances have hitherto been proposed for submuscular injection (Teflon®, Polydimethylsiloxan®, Macroplastique®, collagen (bovine), Zyplast®, autologous chondrocytes, fatty tissue and blood). The preparation Deflux® (dextranomer/hyaluronic acid copolymer) has also since been approved by the FDA (Oswald et al., 2002, Prospective comparison and 1-year follow-up of a single endoscopic subureteral polymethylsiloxane versus dextranomer/hyaluronic acid copolymer injection for treatment of vesicoureteral reflux in children, Urology 2002; 60: 894-7).
Summarizing, it can be said for all the proposed uses that the materials to date for under-injection of polymers have the disadvantage that inflammatory reactions were caused, the materials partially migrated and multiple injections were necessary. These problems are solved in an advantageous manner by the present invention.